Neurodegenerative diseases are associated with conditions in which neuronal cells deteriorate, lose function, and often die. As they are generally progressive, the consequences of neurodegenerative diseases are often devastating. Patients with neurodegenerative disease may suffer severe deterioration in cognitive or motor skills. As a result, their quality of life and life expectancy may be considerably reduced. In humans, these diseases include, but are not limited to, Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease, Fronto-Temporal Dementia, and Cortico Basal Degeneration, among others.
Parkinson's Disease is a progressive disorder that affects brain neuronal cells controlling muscle movement. These neuronal cells make dopamine, which is an important chemical for transmitting signals between cells to facilitate movement of the body. Therefore, the loss of these neurons leads to movement disorders, such as tremor and speech impairment that are typically exhibited by Parkinson's patients. According to the National Institute of Neurological Disorders and Stroke, at least 1 million people suffer from Parkinson's Disease, and about 50,000 new cases are reported each year in the United States.
A highly conserved pre-synaptic protein, α-synuclein, has been implicated in the pathology of Parkinson's Disease. It is thought that conformational changes in α-synuclein lead to the proteinaceous accumulation and fibrillogenesis characteristic of this disease. See U.S. Pat. No. 7,045,290 (to Lindquist et al.). Current treatment options include levodopa and dopamine agonists. These drugs, however, only give temporary relief to the symptoms and have serious side effects if used in large amounts. Deprenyl, a monoamine oxidase B inhibitor, was the first drug suggested to provide causal treatment of Parkinson's Disease by alleviating symptoms and attenuating the progression of the disease, but the therapeutic efficacy of deprenyl is controversial. See U.S. Pat. No. 6,417,177 (to Nelson).
Huntington's Disease (HD) is a genetic neurological disorder, with symptoms of abnormal body movement and impaired mental abilities. Huntington's Disease is caused by a trinucleotide repeat expansion in the Huntingtin gene (htt), which in turn produces a mutant form of the htt protein having an pathological expansion of a polyglutamine (PolyQ) tract. The mutant htt protein misfolds and forms aggregates in the brain and other affected tissues, resulting in neuronal cell death (Wolfgang et al., Proc Nat Acad Sci 2005; 102: 11563-11568). Most of the drugs used to treat the symptoms of Huntington's Disease have side effects such as fatigue, restlessness, or hyperexcitability.
Alzheimer Disease (AD) is a progressive brain disease known generally as senile dementia. More than 4.5 million Americans have been diagnosed with AD, and this number is expected to triple in the next 40-50 years (Lyketsos et al., Am J Geriatr Psychiatry 2006; 14(7): 561-72).
It is believed that the pathophysiological root of Aβ lies, in part, in the misprocessing or mutation of the amyloid precursor protein. The misprocessed protein may produce an increased amount of amyloid beta peptides (Aβ) or variant forms thereof. The accumulation of Aβ leads to the deposition of insoluble Aβ plaques, and eventually to synaptic failure, neuronal injury, formation of tangles of hyperphosphorylated tau protein, and apoptotic neuronal death. The injury or death of neurons leads to the loss of multiple neurotransmitters, which in turn leads to the emergence of the cognitive and functional symptoms of the disease.
Currently available medications offer relatively small symptomatic benefit for some patients and do not slow disease progression. Therefore, various symptomatic strategies for treating or preventing AD are ongoing. For example, AD has been found to be associated with brain inflammation, and thus, nonsteroidal anti-inflammatory drugs such as ibuprofen and indomethacin have been used to lower risk of developing AD. However, the drugs have long-term risks of gastrointestinal bleeding and renal disease, and are associated with rare cardiovascular toxicity. An association of oxygen free radicals with AD has also raised the possibility of antioxidant therapy. The American Psychiatric Association and the American Academy of Neurology Treatment Guidelines for AD both recommend high-doses of vitamin E as a treatment option. This recommendation is tempered, however, by recent findings that vitamin E therapy did not delay progression of mild cognitive impairment associated with AD, and that vitamin E in very high doses increased mortality in older people. See Lyketsos et al., 2006, supra.
Another treatment option for AD is to reduce the naturally occurring degradation of acetylcholine by an enzyme known as acetylcholine esterase (AChE) Inhibition of AChE leads to increased acetylcholine levels. The U.S. Food and Drug Administration has approved four cholinesterase inhibitors drugs for the treatment for Aβ: tacrine, donepezil, rivastigmine, and galanthamine. Short-term (up to 6 months) clinical trials of the cholinesterase inhibitors showed that these drugs improved or slowed cognitive losses associated with AD, but clinical trial results on their long-term benefits are not conclusive. In very mild or more severe AD, the benefits of cholinesterase inhibitors are less substantiated. See Lyketsos et al., 2006, supra.
Treatments of AD that target removing Aβ from the brain are under development. For example, U.S. Pat. No. 7,262,223 (to Kong et al.) describes the use of amidine compounds in the treatment of amyloid-related diseases; U.S. Pat. No. 7,279,501 (to Kim) describes the use of natural product compounds isolated from plants (e.g., turmeric, gingko biloba, and ginger) and their synthetic chemical analogues for the treatment of an Aβ-induced disease. Recent evidence suggests that moderate consumption of red wine may reduce the incidence of AD and may attenuate AD-type cognitive deterioration and amyloid neuropathology (Dartigues et al., Therapie 1993; 48: 185-187; Dorozynski, BMJ 1997; 314: 997; Luchsinger et al., J Am Geriatr Soc 2004; 52: 540-546). Accumulation of soluble extracellular high molecular weight (HMW) oligomeric Aβ species in the brain is considered a major risk factor for the onset and progression of cognitive deterioration (Klyubin et al., Nat Med 2005; 11: 556-561; Selkoe, J Alzheimer's Dis 2001; 3: 75-80). It has also been suggested that grape-derived polyphenolic compounds may inhibit oligomerization of Aβ in vitro (Porat et al., Chem Biol Drug Des 2006; 67: 27-37). However, studies to date were limited to in vitro testing.
Many types of neurodegenerative diseases are linked with abnormal protein folding, accumulation, aggregation, and/or deposition of proteins. For example, there are two types of abnormal protein deposits in the brains of Alzheimer's patients. There are amyloid plaques composed of amyloid beta peptides that are deposited extracellularly in the brain parenchyma and around the cerebral vessel walls, and there are neurofibrillary tangles that are composed of aggregates of hyperphosphorylated tau protein located in the cytoplasm of degenerating neurons. In patients with Parkinson's Disease, Lewy bodies are observed in the cytoplasm of neurons of the substantia nigra. The major constituents of Lewy bodies are fragments of a protein named α-synuclein. In patients with Huntington's disease, intranuclear deposits of a polyglutamine-rich version of the mutant Huntingtin protein are a typical feature of the brain. Patients with hereditary Amyotrophic Lateral Sclerosis have aggregates primarily composed of superoxide dismutase in cell bodies and axons of motor neurons. Additionally, diverse forms of transmissible spongiform encephalopathy are characterized by accumulations of protease-resistant aggregates of the prion protein.
Evidence from biochemical, genetic, and neuropathological studies suggests an active involvement of protein misfolding and/or aggregation in the pathology of neurodegenerative diseases. For example, the presence of abnormal aggregates usually occurs in the brain regions mostly damaged by the disease. Mutations in the gene encoding the misfolded protein produce inherited forms of the disease, which usually have an earlier onset and more severe phenotype than the sporadic forms. Transgenic animals expressing the human mutant gene for the misfolded protein develop some of the typical neuropathological and clinical characteristics of the human disease. Also, misfolded protein aggregates produced in vitro are neurotoxic and induce cell death.
Tauopathies are a family of neurodegenerative diseases that implicate malfunction of tau proteins (a family of closely related intracellular microtubule-associated proteins). These neurodegenerative diseases include, for example, Alzheimer's disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, Argyrophilic Grain Disease, Pick's Disease, as well as others. Common features among tauopathies are abnormal hyperphosphorylation of tau and accumulations of tau into detergent-resistant intracellular inclusions known as neurofibrillary tangles (NFTs) among neurons or glial cells in the brain. Abnormally hyperphosphorylated tau proteins are readily dissociated from microtubules and aggregated into oligomeric tau paired helical filaments that are ultimately deposited as intracellular NFTs. (Mi, K. et al., Curr Alzheimer Res 2006; 3: 449-463). The formation of oligomers serves as nucleation sites that sequester additional hyperphosphorylated tau as well as normal non-phosphorylated tau into fibrillary aggregates. (Sorrentino et al., Neurol Sci 2007; 28: 63-71). Thus, a theory of tau-mediated neurodegeneration is based on a “toxic gain of function” model, in which abnormally phosphorylated tau proteins promote removal of both hyperphosphorylated and normal tau proteins from microtubules. This leads to microtubule instability and alterations of microtubule-mediated processes such as axonal transport, which in turn leads to impaired function and reduced viability of neuronal and glial cells in the brain (Sorrentino et al., 2007, supra).
U.S. Patent Application Publication No. 2007/0122504 (to Moon et al.) discloses a process of manufacturing a grape seed extract and methods of using such grape seed extract to treat neurodegenerative diseases, including AD. The extract is prepared by (1) extracting the grape seed in an alkaline solution having a pH of 8 to 11, at preferably 20-50° C. to obtain alkaline soluble substance; (2) neutralizing with acidic solution to adjust to the pH ranging from 2 to 4, and centrifuging the resulting solution and obtaining precipitated layer; (3) adding lower alcohol and obtaining the supernatant layer, then concentrating the supernatant layer; and (4) adding non-polar solvent and removing non-polar solvent soluble layer to obtain purified fraction and subjecting to repeated purification and lyophilzation to obtain dried grape seed extract. (See Moon, paragraphs [0030]-[0035]).
Due to the prevalence of neurodegenerative disease and the lack of proven effective pharmaceutical compositions or methods to treat symptoms associated with the neurodegenerative diseases, there is still a need for improved pharmaceutical compositions and methods for treatment and prevention thereof.